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The objective of the study was to investigate transcranial wave propagation through two low-intensity focused ultrasound (LIFU)-based brain stimulation techniques-transcranial focused ultrasound stimulation (tFUS) and transcranial pulse stimulation (TPS). Although tFUS involves delivering long trains of acoustic pulses, the newly introduced TPS delivers ultrashort (∼3 μs) pulses repeated at 4 Hz. Accordingly, only a single simulation study with limited geometry currently exists for TPS. We considered a high-resolution three-dimensional (3D) whole human head model in addition to water bath simulations. We anticipate that the results of this study will help researchers investigating LIFU have a better understanding of the effects of the two different techniques.With an objective to first reproduce previous computational results, we considered two spherical tFUS transducers that were previously modeled. We assumed identical parameters (geometry, position, and imaging data set) to demonstrate differences, purely because of the waveform considered. For simulations with a 3D head data set, we also considered a parabolic transducer that has been used for TPS delivery.Our initial results successfully verified previous modeling workflow. The tFUS distribution was characterized by the typical elliptical profile, with its major axis perpendicular to the face of the transducer. The TPS distribution resembled two mirrored meniscus profiles, with its widest diameter oriented parallel to the face of the transducer. The observed intensity value differences were theoretical because the two waveforms differ in both intensity and time. The consideration of a realistic 3D human head model resulted in only a minor distortion of the two waveforms.This study simulated TPS administration using a 3D realistic image-derived data set. Although our comparison results are strictly limited to the model parameters and assumptions made, we were able to elucidate some clear differences between the two approaches. We hope this initial study will pave the way for systematic comparison between the two approaches in the future.

Objective A recently introduced Spinal Cord Stimulation (SCS) system operates at 10 kHz, faster than conventional SCS systems, resulting in significantly more power delivered to tissues. Using a SCS heat phantom and bioheat multi-physics model, we characterized tissue temperature increases by this 10 kHz system. We also evaluated its Implanted Pulse Generator (IPG) output compliance and the role of impedance in temperature increases. Materials and methods The 10 kHz SCS system output was characterized under resistive loads (1-10 KΩ). Separately, fiber optic temperature probes quantified temperature increases (ΔTs) around the SCS lead in specially developed heat phantoms. The role of stimulation Level (1-7; ideal pulse peak-to-peak of 1-7mA) was considered, specifically in the context of stimulation current Root Mean Square (RMS). Data from the heat phantom were verified with the SCS heat-transfer models. A custom high-bandwidth stimulator provided 10 kHz pulses and sinusoidal stimulation for control experiments. Results The 10 kHz SCS system delivers 10 kHz biphasic pulses (30-20-30 μs). Voltage compliance was 15.6V. Even below voltage compliance, IPG bandwidth attenuated pulse waveform, limiting applied RMS. Temperature increased supralinearly with stimulation Level in a manner predicted by applied RMS. ΔT increases with Level and impedance until stimulator compliance was reached. Therefore, IPG bandwidth and compliance dampen peak heating. Nonetheless, temperature increases predicted by bioheat multi-physic models (ΔT = 0.64°C and 1.42°C respectively at Level 4 and 7 at the cervical segment; ΔT = 0.68°C and 1.72°C respectively at Level 4 and 7 at the thoracic spinal cord)-within ranges previously reported to effect neurophysiology. Conclusions Heating of spinal tissues by this 10 kHz SCS system theoretically increases quickly with stimulation level and load impedance, while dampened by IPG pulse bandwidth and voltage compliance limitations. If validated in vivo as a mechanism of kHz SCS, bioheat models informed by IPG limitations allow prediction and optimization of temperature changes.

The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.

Transcranial electrical stimulation (tES) devices apply electrical waveforms through electrodes placed on the scalp to modulate brain function. This chapter describes the principles, types, and components of tES devices as well as practical considerations for their use. All tES devices include a waveform generator, electrodes, and an adhesive or headgear to position the electrodes. tES dose is defined by the size and position of electrodes, and the waveform, duration, and intensity of the current. Many sub-classes of tES are named based on dose. This chapter focuses on low intensity tES, which includes transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial pulsed current stimulation (tPCS). tES electrode types are reviewed, including electrolyte-soaked sponge, adhesive hydrogel, high-definition, hand-held solid metal, free paste on electrode, and dry. Computational models support device design and individual targeting. The tolerability of tES is protocol specific, and medical grade devices minimize risk.

The behavioural variant of frontotemporal dementia is a neurodegenerative disease characterized by bilateral atrophy of the prefrontal cortex, gradual deterioration of behavioural and executive capacities, a breakdown of language initiation and impaired search mechanisms in the lexicon. To date, only a few studies have analysed the modulation of language deficits in the behavioural variant of frontotemporal dementia patients with transcranial direct current stimulation, yet with inconsistent results. Our goal was to assess the impact on language performance of a single session of transcranial direct current stimulation on patients with the behavioural variant of frontotemporal dementia. Using a sham-controlled double-blind crossover design in a cohort of behavioural frontotemporal dementia patients (n = 12), we explored the impact on language performance of a single transcranial direct current stimulation session delivering anodal or cathodal transcranial direct current stimulation, over the left and right dorsolateral prefrontal cortex, compared with sham stimulation. A Letter fluency and a Picture naming task were performed prior and following transcranial direct current stimulation, to assess modulatory effects on language. Behavioural frontotemporal dementia patients were impaired in all evaluation tasks at baseline compared with healthy controls. Computational finite element method (FEM) models of cortical field distribution corroborated expected impacts of left-anodal and right-cathodal transcranial direct current stimulation over the dorsolateral prefrontal cortex and showed lower radial field strength in case of atrophy. However, none of the two tasks showed statistically significant evidence of language improvement caused by active transcranial direct current stimulation compared with sham. Our findings do not argue in favour of pre-therapeutic effects and suggest that stimulation strategies evaluating the modulatory role of transcranial direct current stimulation in the behavioural variant of frontotemporal dementia must carefully weigh the influence of symptom severity and cortical atrophy affecting prefrontal regions to ensure clinical success.

Galvanic vestibular stimulation (GVS) involves the application of electrical current through electrodes placed exclusively at the mastoids or in combination with electrodes placed on other regions. It is a simple, safe modality to modulate and probe vestibular function. Despite a long history of use, it continues to be primarily used as a research tool with no fully developed therapeutic use. This is partly due to the fact that to further advance this technique, a better understanding of what structures are stimulated and by how much is needed. While models have been proposed to explain response, cellular and structural substrates confirmed empirically, the exact current flow pattern has not been investigated.The goal of this study is to therefore determine current flow patterns in GVS. In order to do so, we developed the first ultrahigh-resolution finite element model of GVS incorporating the tiny structures of interest in the inner ear. We simulated the Bilateral-Bipolar, Bilateral-Monopolar, and the Unilateral-Monopolar configurations. Specifically, we generated surface electric field magnitude plots for the brain and for structures considered most relevant to GVS mechanism of action- the semi-circular canals (SCC) and the otolith.Findings show that the Bilateral-Bipolar configuration results in the most spatially restricted flow while the Unilateral-Monopolar configuration results in the most diffuse. With respect to SCC and the otolith, both Bilateral-Bipolar and Bilateral-Monopolar configurations led to similar flow in both the left and right pairs. For the Unilateral-Monopolar configuration, we observed increased flow in the left pair.We expect via this first model developed for GVS, researchers investigating this technique to have a better understanding of the effects of different configurations. Anatomically detailed models like these may also help understand the mechanism of action and may guide the rational design of future GVS administration.

Cervical injuries are the most common form of SCI. In this study, we used a neuromodulatory approach to promote skilled movement recovery and repair of the corticospinal tract (CST) after a moderately severe C4 midline contusion in adult rats. We used bilateral epidural intermittent theta burst (iTBS) electrical stimulation of motor cortex to promote CST axonal sprouting and cathodal trans-spinal direct current stimulation (tsDCS) to enhance spinal cord activation to motor cortex stimulation after injury. We used Finite Element Method (FEM) modeling to direct tsDCS to the cervical enlargement. Combined iTBS-tsDCS was delivered for 30 min daily for 10 days. We compared the effect of stimulation on performance in the horizontal ladder and the Irvine Beattie and Bresnahan forepaw manipulation tasks and CST axonal sprouting in injury-only and injury + stimulation animals. The contusion eliminated the dorsal CST in all animals. tsDCS significantly enhanced motor cortex evoked responses after C4 injury. Using this combined spinal-M1 neuromodulatory approach, we found significant recovery of skilled locomotion and forepaw manipulation skills compared with injury-only controls. The spared CST axons caudal to the lesion in both animal groups derived mostly from lateral CST axons that populated the contralateral intermediate zone. Stimulation enhanced injury-dependent CST axonal outgrowth below and above the level of the injury. This dual neuromodulatory approach produced partial recovery of skilled motor behaviors that normally require integration of posture, upper limb sensory information, and intent for performance. We propose that the motor systems use these new CST projections to control movements better after injury.

Objective Understanding how current reaches the brain during transcranial electrical stimulation (tES) underpins efforts to rationalize outcomes and optimize interventions. To this end, computational models of current flow relate applied dose to brain electric field. Conventional tES modeling considers distinct tissues like scalp, skull, cerebrospinal fluid (CSF), gray matter and white matter. The properties of highly conductive CSF are especially important. However, modeling the space between skull and brain as entirely CSF is not an accurate representation of anatomy. The space conventionally modeled as CSF is approximately half meninges (dura, arachnoid, and pia) with lower conductivity. However, the resolution required to describe individual meningeal layers is computationally restrictive in an MRI-derived head model. Emulating the effect of meninges through CSF conductivity modification could improve accuracy with minimal cost. Approach Models with meningeal layers were developed in a concentric sphere head model. Then, in a model with only CSF between skull and brain, CSF conductivity was optimized to emulate the effect of meningeal layers on cortical electric field for multiple electrode positions. This emulated conductivity was applied to MRI-derived models. Main results Compared to a model with conventional CSF conductivity (1.65 S m-1), emulated CSF conductivity (0.85 S m-1) produced voltage fields better correlated with intracranial recordings from epilepsy patients. Significance Conventional tES models have been validated using intracranial recording. Residual errors may nonetheless impact model utility. Because CSF is so conductive to current flow, misrepresentation of the skull-brain interface as entirely CSF is not realistic for tES modeling. Updating the conventional model with a CSF conductivity emulating the effect of the meninges enhances modeling accuracy without increasing model complexity. This allows existing modeling pipelines to be leveraged with a simple conductivity change. Using 0.85 S m-1 emulated CSF conductivity is recommended as the new standard in non-invasive brain stimulation modeling.

Background: During transcranial direct current stimulation (tDCS), the amount and distribution of current that reaches the brain depends on individual anatomy. Many progressive neurodegenerative diseases are associated with cortical atrophy, but the importance of individual brain atrophy during tDCS in patients with progressive atrophy, including primary progressive aphasia (PPA), remains unclear. Objective: In the present study, we addressed the question whether brain anatomy in patientswith distinct cortical atrophy patterns would impact brain current intensity and distribution during tDCS over the left IFG. Method: We developed state-of-the-art, gyri-precise models of three subjects, each representing a variant of primary progressive aphasia: non-fluent variant PPA (nfvPPA), semantic variant PPA (svPPA), and logopenic variant PPA (lvPPA). We considered two exemplary montages over the left inferior frontal gyrus (IFG): a conventional pad montage (anode over F7, cathode over the right cheek) and a 4 × 1 high-definition tDCS montage. We further considered whether local anatomical features, specifically distance of the cortex to skull, can directly predict local electric field intensity. Results: We found that the differences in brain current flow across the three PPA variants fall within the distribution of anatomically typical adults. While clustering of electric fields was often around individual gyri or sulci, the minimal distance from the gyri/sulci to skull was not correlated with electric field intensity. Conclusion: Limited to the conditions and assumptions considered here, this argues against a specific need to adjust the tDCS montage for these patients any more than might be considered useful in anatomically typical adults. Therefore, local atrophy does not, in isolation, reliably predict local electric field. Rather, our results are consistent with holistic head anatomy influencing brain current flow, with tDCS producing diffuse and individualized brain current flow patterns and HD-tDCS producing targeted brain current flow across individuals.

Although specific brain regions are important for regularly patterned limb movements, the rhythm generation system that governs bipedal locomotion in humans is not thoroughly understood. We investigated whether rhythmic transcranial brain stimulation over the cerebellum could alter walking rhythm. Fourteen healthy subjects performed over-ground walking for 10 min during which they were given, in a random order, transcranial alternating current stimulation (tACS) over the left cerebellum at the approximated frequency of their gait cycle, tACS over the skin of the scalp, and during sham stimulation. Cerebellar tACS showed a significant entrainment of gait rhythm compared with the control conditions. When the direction of the tACS currents was symmetrically inverted, some subjects showed entrainment at an approximately 180° inverted phase, suggesting that gait modulation is dependent on current orientation. These findings indicate that tACS over cerebellum can modulate gait generation system in cerebellum and become an innovative approach for the recovery of locomotion in patients with gait disturbances caused by CNS disorders.

Transcranial Direct Current Stimulation (tDCS) dose designs are often based on computational Finite Element Method (FEM) forward modeling studies. These FEM models educate researchers about the resulting current flow (intensity and pattern) and so the resulting neurophysiological and behavioral changes based on tDCS dose (mA), resistivity of head tissues (e.g. skin, skull, CSF, brain), and head anatomy. Moreover, model support optimization of montage to target specific brain regions. Computational models are thus an ancillary tool used to inform the design, set-up and programming of tDCS devices, and investigate the role of parameters such as electrode assembly, current directionality, and polarity of tDCS in optimizing therapeutic interventions. Computational FEM modeling pipeline of tDCS initiates with segmentation of an exemplary magnetic resonance imaging (MRI) scan of a template head into multiple tissue compartments to develop a higher resolution (< 1 mm) MRI derived FEM model using Simpleware ScanIP. Next, electrode assembly (anode and cathode of variant dimension) is positioned over the brain target and meshed at different mesh densities. Finally, a volumetric mesh of the head with electrodes is imported in COMSOL and a quasistatic approximation (stead-state solution method) is implemented with boundary conditions such as inward normal current density (anode), ground (cathode), and electrically insulating remaining boundaries. A successfully solved FEM model is used to visualize the model prediction via different plots (streamlines, volume plot, arrow plot).

This chapter provides a broad introduction to computational models that inform and optimize tDCS for both clinical researchers and translational engineers. The first section introduces the rationale for modeling; the next two sections address technical features of modeling relevant to engineers (and to clinicians interested in the limitations of modeling); the following three sections address the use of modeling in clinical practice, and the final section illustrates the application of models in dose design through case studies. Computational “forward” models predict the flow of current throughout the head during tDCS, as with other brain stimulation techniques. Because the relationship between stimulation dose (defined as those electrode and waveform parameters controlled by the operator) and resulting brain current flow is complex and non-intuitive, computational forward models are essential to the rational design of stimulation protocols. Though model validation efforts are ongoing, these models already represent a standard tool to predict brain current flow and optimize tDCS dose, and so inform clinical practice and behavior research. Yet despite increased interest in tDCS modeling, as supported by the number of tDCS publications about or including a modeling component, access to modeling tools by clinicians remains highly limited. Ironically, much of the effort to enhance the relevance of modeling through increased sophistication (complexity) in fact hinders both reproduction and dissemination. This chapter therefore addresses not only the state-of-the-art in modeling techniques, but also how models can be immediately leveraged by researchers and clinicians.

The stimulation parameters for transcranial direct current stimulation (tDCS), called stimulation dose, are straightforward and are summarized in this chapter. tDCS dose is set by the stimulation current, duration, and electrode montage. And yet it is necessary to emphasize that the apparent simplicity of describing tDCS dose (1) cannot supplement using poorly designed equipment, head-gear, or electrodes and (2) is no justification for insufficient training of operators including electrode preparation. Proper equipment and rigorous training is critical for reproducibility of dose and tolerability, and so a trial that reports dose but fails to consider how to implement that dose through equipment and protocols may not be reproducible (as further discussed in Chaps. 7 and 10), including critical considerations for home use (Chap. 13). Despite the apparent simplicity of tDCS dose there is tremendous potential for flexibility and customization of tDCS: any current can be combined with any duration, with many permutations of electrode montage. There is tremendous sophistication in the design of tDCS dose including leveraging computational models of current flow (Chap. 4) and neurons (Chap. 2) or imaging (Chap. 11). The issues surrounding the selection of stimulation parameters and ensuring they are rigorously applied are thus addressed throughout this book, and this chapter only emphasizes what those parameters are, and additional factors related to tolerability.

Despite promising preliminary results in treating fibromyalgia (FM) pain, no neuromodulation technique has been adopted in clinical practice because of limited efficacy, low response rate, or poor tolerability. This phase II open-label trial aims to define a methodology for a clinically effective treatment of pain in FM by establishing treatment protocols and screening procedures to maximize efficacy and response rate. High-definition transcranial direct current stimulation (HD-tDCS) provides targeted subthreshold brain stimulation, combining tolerability with specificity. We aimed to establish the number of HD-tDCS sessions required to achieve a 50% FM pain reduction, and to characterize the biometrics of the response, including brain network activation pain scores of contact heat-evoked potentials. We report a clinically significant benefit of a 50% pain reduction in half (n = 7) of the patients (N = 14), with responders and nonresponders alike benefiting from a cumulative effect of treatment, reflected in significant pain reduction ( P = .035) as well as improved quality of life ( P = .001) over time. We also report an aggregate 6-week response rate of 50% of patients and estimate 15 as the median number of HD-tDCS sessions to reach clinically meaningful outcomes. The methodology for a pivotal FM neuromodulation clinical trial with individualized treatment is thus supported. Online Registration Registered in Clinicaltrials.gov under registry number NCT01842009. Perspective In this article, an optimized protocol for the treatment of fibromyalgia pain with targeted subthreshold brain stimulation using high-definition transcranial direct current stimulation is outlined.

Objective There is a long interest in using EEG measurements to inform transcranial Electrical Stimulation (tES) but adoption is lacking. The conventional approach is to use anatomical head-models for both source localization (the EEG inverse problem) and current flow modeling (the tES forward model), but this approach is computationally demanding, requires an anatomical MRI, and strict assumptions about the target brain regions. We evaluate techniques whereby tES dose is derived from EEG without the need for an anatomical head model or assumptions. Approach The approaches are verified using a Finite Element Method (FEM) simulation of the EEG generated by a dipole, oriented either tangential or radial to the surface, and then simulating brain current flow produced by various model-free techniques including: (1) Voltage-to-voltage, (2) Voltage-to-Current; (3) Laplacian; and two Ad-Hoc techniques (4) Dipole sink-to-sink; and (5) Sink to Concentric Ring. These model-free approaches are compared to a numerically optimized dose that assumes perfect understanding of the dipole location and head anatomy. We vary the number of electrodes from a few to over three hundred, with focality or intensity as optimization criterion. Main results Our results demonstrate how simple Ad-Hoc approaches can achieve reasonable targeting for the case of a cortical dipole with 2–8 electrodes and no need for a model of the head. Significance For its simplicity and linearity, model-free EEG guided lends itself to broad adoption and can be applied to a static (tDCS), time-variant (e.g. tACS, tRNS, tPCS), or closed-loop tES. Figure options Download full-size image Download high-quality image (1118 K) Download as PowerPoint slide Figure options Download full-size image Download high-quality image (1499 K) Download as PowerPoint slide

Background Quasi-uniform assumption is a general theory that postulates local electric field predicts neuronal activation. Computational current flow model of spinal cord stimulation (SCS) of humans and animal models inform how the quasi-uniform assumption can support scaling neuromodulation dose between humans and translational animal. New method Here we developed finite element models of cat and rat SCS, and brain slice, alongside SCS models. Boundary conditions related to species specific electrode dimensions applied, and electric fields per unit current (mA) predicted. Results Clinically and across animal, electric fields change abruptly over small distance compared to the neuronal morphology, such that each neuron is exposed to multiple electric fields. Per unit current, electric fields generally decrease with body mass, but not necessarily and proportionally across tissues. Peak electric field in dorsal column rat and cat were ∼17x and ∼1x of clinical values, for scaled electrodes and equal current. Within the spinal cord, the electric field for rat, cat, and human decreased to 50% of peak value caudo-rostrally (C5–C6) at 0.48 mm, 3.2 mm, and 8 mm, and mediolaterally at 0.14 mm, 2.3 mm, and 3.1 mm. Because these space constants are different, electric field across species cannot be matched without selecting a region of interest (ROI). Comparison with existing method This is the first computational model to support scaling neuromodulation dose between humans and translational animal. Conclusions Inter-species reproduction of the electric field profile across the entire surface of neuron populations is intractable. Approximating quasi-uniform electric field in a ROI is a rational step to translational scaling.

Transcranial direct current stimulation (tDCS) devices apply direct current through electrodes on the scalp with the intention to modulate brain function for experimental or clinical purposes. All tDCS devices include a current controlled stimulator, electrodes that include a disposable electrolyte, and headgear to position the electrodes on the scalp. Transcranial direct current stimulation dose can be defined by the size and position of electrodes and the duration and intensity of current applied across electrodes. Electrode design and preparation are important for reproducibility and tolerability. High-definition tDCS uses smaller electrodes that can be arranged in arrays to optimize brain current flow. When intended to be used at home, tDCS devices require specific device design considerations. Computational models of current flow have been validated and support optimization and hypothesis testing. Consensus on the safety and tolerability of tDCS is protocol specific, but medical-grade tDCS devices minimize risk.

Background and Objective. Tinnitus is the perception of a phantom sound. The aim of this study was to compare current intensity (center anode 1 mA and 2 mA), duration (10 minutes and 20 minutes), and location (left temporoparietal area [LTA] and dorsolateral prefrontal cortex [DLPFC]) using 4 × 1 high-definition transcranial direct current stimulation (HD-tDCS) for tinnitus reduction. Methods. Twenty-seven participants with chronic tinnitus (>2 years) and mean age of 53.5 years underwent 2 sessions of HD-tDCS of the LTA and DLPFC in a randomized order with a 1 week gap between site of stimulation. During each session, a combination of 4 different settings were used in increasing dose (1 mA, 10 minutes; 1 mA, 20 minutes; 2 mA, 10 minutes; and 2 mA, 20 minutes). The impact of different settings on tinnitus loudness and annoyance was documented. Results. Twenty-one participants (77.78%) reported a minimum of 1 point reduction on tinnitus loudness or annoyance scales. There were significant changes in loudness and annoyance for duration of stimulation, F(1, 26) = 10.08, P < .005, and current intensity, F(1, 26) = 14.24, P = .001. There was no interaction between the location, intensity, and duration of stimulation. Higher intensity (2 mA) and longer duration (20 minutes) of stimulation were more effective. Conclusions. A current intensity of 2 mA for 20-minute duration was the most effective setting used for tinnitus relief. The stimulation of the LTA and DLPFC were equally effective for suppressing tinnitus loudness and annoyance.

Chronic pain impacts approximately 100 million people in the United States with annual costs more than $635 billion [1]. Fibromyalgia (FM) is considered the prototypical central pain syndrome and emerging data suggests that there are central nervous system alterations in FM patients [2-4]. Despite the presence of multiple treatments for this condition, many FM patients still report significant unresolved pain and disability. A significant limitation to evaluating potential interventions for chronic pain syndromes, including FM, is the lack of an objective marker of pain. There has been significant interest in using neuroimaging methods to develop an objective test of pain such as proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS is able to measure brain metabolite levels including γ–aminobutyric acid (GABA), the brain’s major inhibitory neurotransmitter, Glx, a combined marker of glutamine and glutamate (the latter being the brain’s major excitatory neurotransmitter), and N-acetylaspartate (NAA), thought to be a measure of neuronal integrity. Our group has reported increased levels of Glx in FM subjects in the posterior insula which is responsible for the graded sensory processing of pain [5, 6]. Our group has also reported decreased levels of GABA in FM subjects in the anterior insula which is important in the emotional processing and affective aspects of pain [6, 7]. Lower NAA levels within the hippocampus has also been reported in the setting of FM [8]. One potential treatment for FM is transcranial direct current stimulation (tDCS). tDCS is a brain stimulating procedure that uses noninvasive weak direct current applied to the scalp. tDCS in FM, as well as other pain conditions, has been shown to modulate experimental and clinical pain measures. Specifically, tDCS has been shown to improve pain symptomatology in FM [9, 10]. Anodal stimulation from tDCS has been shown to increase cortical excitability which is postulated to mitigate pain symptoms through indirect effects on pain processing regions in the brain [9]. However, the mechanisms underlying tDCS efficacy in chronic pain are not well understood, and chronic pain trials using tDCS have not reported consistent results [11]. Our objective was to explore the underlying neurochemical action of tDCS in the FM brain using 1H-MRS.

Background Monitoring of electrode resistance during tDCS is considered important for tolerability and safety. Conventional resistance measurement methods do not isolate individual electrode resistance and for HD-tDCS devices, cross talk across electrodes makes concurrent resistance monitoring unreliable. Objective We propose a novel method to monitor individual electrode resistance during tDCS, using a super-position of direct current with a test-signal (low intensity and low frequency sinusoids with electrode–specific frequencies) and a sentinel electrode (not used for DC). Methods We developed and solved lumped-parameter models of tDCS electrodes with or without a sentinel electrode to validate this methodology. Assumptions were tested and parameterized in participants using forearm stimulation combining tDCS (2 mA) and test-signals (38 and 76 μA pk-pk at 1 Hz, 10 Hz, & 100 Hz) and an in vitro test (creating electrode failure modes). DC and AC component voltages across the electrodes were compared and participants were asked to rate subjective pain. Results A sentinel electrode is required to isolate electrode resistance in a two-electrode tDCS system. Cross talk aggravated with electrode proximity and resistance mismatch in multi-electrode resistance tracking could be corrected using proposed approaches. Average voltage and pain scores were not significantly different across test current intensities and frequencies. Conclusion Using our developed method, a test signal can predict DC electrode resistance. Since unique test frequencies can be used at each tDCS electrode, specific electrode resistance can be resolved for any number of stimulating channels - a process made still more robust by the use of a sentinel electrode.

CONTEXT AND OBJECTIVE: Patients undergoing the same neuromodulation protocol may present different responses. Computational models may help in understanding such differences. The aims of this study were, firstly, to compare the performance of aphasic patients in naming tasks before and after one session of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS) and sham, and analyze the results between these neuromodulation techniques; and secondly, through computational model on the cortex and surrounding tissues, to assess current flow distribution and responses among patients who received tDCS and presented different levels of results from naming tasks. DESIGN AND SETTING: Prospective, descriptive, qualitative and quantitative, double blind, randomized and placebo-controlled study conducted at Faculdade de Ciências Médicas da Santa Casa de São Paulo. METHODS: Patients with aphasia received one session of tDCS, TMS or sham stimulation. The time taken to name pictures and the response time were evaluated before and after neuromodulation. Selected patients from the first intervention underwent a computational model stimulation procedure that simulated tDCS. RESULTS: The results did not indicate any statistically significant differences from before to after the stimulation.The computational models showed different current flow distributions. CONCLUSIONS: The present study did not show any statistically significant difference between tDCS, TMS and sham stimulation regarding naming tasks. The patients’responses to the computational model showed different patterns of current distribution.

Objectives Non-invasive transcranial direct current stimulation (tDCS) over the motor cortex is broadly investigated to modulate functional outcomes such as motor function, sleep characteristics, or pain. The most common montages that use two large electrodes (25-35 cm2 ) placed over the area of motor cortex and contralateral supraorbital region (M1-SO montages) require precise measurements, usually using the 10-20 EEG system, which is cumbersome in clinics and not suitable for applications by patients at home. The objective was to develop and test novel headgear allowing for reproduction of the M1-SO montage without the 10-20 EEG measurements, neuronavigation, or TMS. Materials and methods Points C3/C4 of the 10-20 EEG system is the conventional reference for the M1 electrode. The headgear was designed using an orthogonal, fixed-angle approach for connection of frontal and coronal headgear components. The headgear prototype was evaluated for accuracy and replicability of the M1 electrode position in 600 repeated measurements compared to manually determined C3 in 30 volunteers. Computational modeling was used to estimate brain current flow at the mean and maximum recorded electrode placement deviations from C3. Results The headgear includes navigational points for accurate placement and assemblies to hold electrodes in the M1-SO position without measurement by the user. Repeated measurements indicated accuracy and replicability of the electrode position: the mean [SD] deviation of the M1 electrode (size 5 × 5 cm) from C3 was 1.57 [1.51] mm, median 1 mm. Computational modeling suggests that the potential deviation from C3 does not produce a significant change in brain current flow. Conclusions The novel approach to M1-SO montage using a fixed-angle headgear not requiring measurements by patients or caregivers facilitates tDCS studies in home settings and can replace cumbersome C3 measurements for clinical tDCS applications.

Background Measurements and models of current flow in the brain during transcranial Direct Current Stimulation (tDCS) indicate stimulation of regions in-between electrodes. Moreover, the folded cortex results in local fluctuations in current flow intensity and direction, and animal studies suggest current flow direction relative to cortical columns determines response to tDCS. Methods Here we test this idea by using Transcranial Magnetic Stimulation Motor Evoked Potentials (TMS-MEP) to measure changes in corticospinal excitability following tDCS applied with electrodes aligned orthogonal (across) or parallel to M1 in the central sulcus. Results Current flow models predicted that the orthogonal electrode montage produces consistently oriented current across the hand region of M1 that flows along cortical columns, while the parallel electrode montage produces non-uniform current directions across the M1 cortical surface. We find that orthogonal, but not parallel, orientated tDCS modulates TMS-MEPs. We also show modulation is sensitive to the orientation of the TMS coil (PA or AP), which is thought to select different afferent pathways to M1. Conclusions Our results are consistent with tDCS producing directionally specific neuromodulation in brain regions in-between electrodes, but shows nuanced changes in excitability that are presumably current direction relative to column and axon pathway specific. We suggest that the direction of current flow through cortical target regions should be considered for targeting and dose-control of tDCS., Highlights • Direction of current flow is important for tDCS after-effects. • tDCS modulates excitability between two electrodes. • tDCS differentially modulates PA and AP inputs into M1.

Objectives To develop the first high-resolution, multi-scale model of cervical non-invasive vagus nerve stimulation (nVNS) and to predict vagus fiber type activation, given clinically relevant rheobase thresholds. Methods An MRI-derived Finite Element Method (FEM) model was developed to accurately simulate key macroscopic (e.g., skin, soft tissue, muscle) and mesoscopic (cervical enlargement, vertebral arch and foramen, cerebral spinal fluid [CSF], nerve sheath) tissue components to predict extracellular potential, electric field (E-Field), and activating function along the vagus nerve. Microscopic scale biophysical models of axons were developed to compare axons of varying size (Aα-, Aβ- and Aδ-, B-, and C-fibers). Rheobase threshold estimates were based on a step function waveform. Results Macro-scale accuracy was found to determine E-Field magnitudes around the vagus nerve, while meso-scale precision determined E-field changes (activating function). Mesoscopic anatomical details that capture vagus nerve passage through a changing tissue environment (e.g., bone to soft tissue) profoundly enhanced predicted axon sensitivity while encapsulation in homogenous tissue (e.g., nerve sheath) dulled axon sensitivity to nVNS. Conclusions These findings indicate that realistic and precise modeling at both macroscopic and mesoscopic scales are needed for quantitative predictions of vagus nerve activation. Based on this approach, we predict conventional cervical nVNS protocols can activate A- and B- but not C-fibers. Our state-of-the-art implementation across scales is equally valuable for models of spinal cord stimulation, cortex/deep brain stimulation, and other peripheral/cranial nerve models.

Understanding which cellular compartments are influenced during neuromodulation underpins any rational effort to explain and optimize outcomes. Axon terminals have long been speculated to be sensitive to polarization, but experimentally informed models for CNS stimulation are lacking. We conducted simultaneous intracellular recording from the neuron soma and axon terminal (blebs) during extracellular stimulation with weak sustained (DC) uniform electric fields in mouse cortical slices. Use of weak direct current stimulation (DCS) allowed isolation and quantification of changes in axon terminal biophysics, relevant to both suprathreshold (e.g., deep brain stimulation, spinal cord stimulation, and transcranial magnetic stimulation) and subthreshold (e.g., transcranial DCS and transcranial alternating current stimulation) neuromodulation approaches. Axon terminals polarized with sensitivity (mV of membrane polarization per V/m electric field) 4 times than somas. Even weak polarization (